RANDOMIZED TRIAL TO EVALUATE THE VIROLOGIC RESPONSE AND PHARMACOKINETICS OF TWO DIFFERENT POTENT REGIMENS IN HIV INFECTED WOMEN

Westat, Inc., Rockville MD

Investigators

Abstract

The current prevention of mother to child transmission (PMTCT) strategies based on the use of triple ARV regimens after the first trimester through labor, appropriate management of delivery, and avoidance of breastfeeding have been successful in lowering the rates of HIV perinatal transmission to less than 2%. Results of clinical trials for PMTCT suggest that women receiving triple antiretroviral (ARV) regimens that effectively reduce HIV-1 Ribonucleic Acid (RNA) to <1,000 copies/mL or undetectable levels are associated with significantly lower risk of perinatal HIV-1 transmission. Published data from a study in a cohort of HIV-infected pregnant women from the United Kingdom and Ireland in which the transmission rate was only 0.1% in 2,117 pregnant women on triple ARV regimens who achieved viral suppression. Also, there is evidence that being on a triple ARV regimen at conception and starting a triple ARV regimen earlier in pregnancy are associated with a lower risk of transmission after adjusting for viral load. This strategy is strongly dependent on early access to prenatal care and availability of ARVs for PMTCT with viral suppression and appropriate approach of mode of delivery. A considerable number of pregnant women enter prenatal care after the 20th to 28th week of gestation even in developed countries. Approximately one quarter of HIV-infected persons in the United States (US) are unaware that they are infected. The Mother-Infant Rapid Intervention at Delivery (MIRIAD) study, which was a prospective, multicenter study funded by the Centers for Disease Control and Prevention, offered voluntary, rapid HIV testing to women with undocumented HIV status late in pregnancy. Among 7,753 women with available test results from17 US hospitals, 52 (0.7%) were HIV-infected. Brazilian data published in 2007 from a cohort of HIV-infected pregnant women at a public hospital showed that the mean gestational age of initiation of prenatal care was 24 ± 8 weeks of gestation. Also, some pregnant women seroconvert late during pregnancy. A Brazilian study addressing primary HIV-1 infection during pregnancy showed an incidence of HIV-1 seroconversion of 0.8/1,000 (CI 95% 0.4-1.5/1,000). These women are more likely to transmit infection to their newborn, as plasma viral loads directly correlate with the risk of mother-to-child transmission (MTCT) of HIV-1. Decay dynamics of HIV-1 depend on the inhibited stage of the viral life cycle and are used as a measure of the effectiveness of ARV drugs and drug regimens. Therefore, the viral decay dynamics provided by different ARVs combinations could be critical for the effectiveness of the PMTCT effort. A more rapid reduction in viral load may be critical in minimizing both trans placental and intrapartum transmission of HIV-1 to the infant if ARV treatment is initiated late in pregnancy. Much virologic, immunologic and tolerability data derived from prospective clinical trials have shown the efficacy of various combinations of ARVs to treat HIV-1 infection. Most of these studies were done in HIV-infected adults with the primary efficacy outcomes based on the decline of plasma viral load within the first 20-48 weeks of starting therapy and on the durability of the virologic response, as well as changes in Cluster of Differentiation 4 (CD4+) T-cell counts aft 48 weeks of therapy. Suppressive ARV regimens containing the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) efavirenz have been extensively studied in non-pregnant adults, demonstrating rapid reduction in plasma HIV viral load. ARVs in the newest class to be approved, integrase inhibitors (IIs), have proven to be very potent in pre-clinical, and phase II and III clinical studies in adult participants, are generally well tolerated, and demonstrate strong efficacy with rapid reduction in plasma viral load in both treatment-naïve and treatment experienced participants. HIV-infected pregnant women presenting for care late in pregnancy need a rapid response and effective ART to minimize the risk of HIV transmission to their newborn. No data are available comparing the effects of NNRTIs and IIs in pregnant women. The goal of this protocol is to compare the safety, tolerance, virologic and pharmacologic responses of representatives of these two ARV classes in HIV-infected pregnant women presenting late for care.